The main aims of this projects are to identify the genetic and/or molecular cause(s) of obesity in humans. We are sequencing obesity target genes to find polymorphisms that may be associated with obesity in a group of 20 prepubertal Pima Indian cases (selected for early onset of severe obesity) and 20 sex- and age-matched lean controls. In the past year we have studied the melanocortin receptor-4 and found no polymorphisms of interest. Sequencing of the the neuropeptide Y receptor-5, has confirmed several polymorphisms previously found to be associated with obesity in adult Pimas. We are also studying differential gene expression in post-mortem brain samples from obese and lean adult donors, using a human neurobiology microarray. In the past year we have completed a study to test the reliability of the methodology, which appears to be acceptable. To uncover possible common neurochemical defects underlying hyperphagia/obesity, we plan to begin by studying differential gene expression in the hypothalamus (which controls many aspects of eating behavior in animals and humans). We have completed one such experiment in 1 obese and 1 lean donor.